Addiction to cocaine remains a serious unmet medical need for which there is no truly effective treatment. Addiction to cocaine an relapse following withdrawal of the drug are associated with changes in CNS glutamate levels and homeostasis. It has been demonstrated that Ceftriaxone, a cephalosporin antibiotic, increases the expression and function of the major glutamate transporter GLT 1 (Rothstein et al, 2005). Ceftriaxone has also been shown to increase the activity of system xC-, which exchanges extracellular cysteine for intracellular glutamate (Lewerenz et al, 2009). Basal non-synaptic glutamate levels in the nucleus accumbens are largely controlled by system xC-, and a decrease in its activity is the cause of the altered glutamate homeostasis observed in this brain region following cocaine self-administration and extinction training in rats (Baker et al, 2003). The catalytic subunit of xC- is xCT, and we have demonstrated that expression of xCT and GLT-1 are decreased in the nucleus accumbens core following cocaine self- administration (Knackstedt et al, 2010a). We have also shown that Ceftriaxone attenuates cue- and cocaine- primed reinstatement while restoring levels of both xCT and GLT-1 in the nucleus accumbens core (Knackstedt et al, 2010a). Furthermore, the protective effect of Ceftriaxone against relapse lasts for weeks following the last administration of Ceftriaxone (Sondheimer & Knackstedt, 2011). While Ceftriaxone shows preclinical promise as a medication for the treatment of cocaine addiction in humans, it possesses several characteristics that may prevent it from translating from the bench to the clinic. As an antibiotic, it possesses antimicrobial activity and thus chronic use of ceftriaxone can induce resistant strains of bacteria. At the high doses required to achieve therapeutically meaningful CNS concentrations (due to Ceftriaxone's low brain bioavailability), chronic Ceftriaxone will likely produce undesirable side effects such a diarrhea. Additionally, Ceftriaxone requires parenteral infusion and it is unlikely that cocaine dependent-patients would comply with daily intravenous administration of Ceftriaxone. We have recently identified MC-100093, a lead molecule from a series of monocyclic azetadinones, as a potent up-regulator of GLT-1 expression that is orally bioavailable, brain penetrant, and induces GLT-1 up-regulation in an accepted model of cocaine addiction and withdrawal. This proposal aims to further optimize the chemical scaffold represented by MC-100093 using a well-defined screening scheme and a multidimensional approach to arrive at one or more advanced lead molecules that can be advanced to IND-enabling studies.